Fibroblast growth factors (FGFs) comprise a family of 22 structurally related polypeptides with diverse biological activities; most of these signaling molecules function by binding to and activating their cognate receptors (FGFRs; designated FGFR1-4), a family of receptor tyrosine kinases (Eswarakumar et al., 2005; Ornitz and Itoh, 2001). These receptor-ligand interactions result in receptor dimerization and autophosphorylation, formation of complexes with membrane-associated and cytosolic accessory proteins, and initiation of multiple signaling cascades (Powers et al., 2000). The FGFR-FGF signaling system plays important roles in development and tissue repair by regulating cellular functions/processes such as growth, differentiation, migration, morphogenesis, and angiogenesis.
Alterations in FGFRs (i.e. overexpression, mutation, translocation, and truncation) are associated with a number of human cancers, including myeloma breast, stomach, colon, bladder, pancreatic, and hepatocellular carcinomas (Bange et al., 2002; Cappellen et al., 1999; Chesi et al., 2001; Chesi et al., 1997; Gowardhan et al., 2005; Jaakkola et al., 1993; Jang et al., 2001; Jang et al., 2000; Jeffers et al., 2002; Xiao et al., 1998). Hepatocellular carcinoma (HCC) is one of the leading global causes of cancer related deaths, resulting in over half a million fatalities per year (Shariff et al., 2009). While the role of FGFR4 in cancer remains to be fully elucidated, several findings suggest that this receptor may be an important player in HCC development and/or progression. FGFR4 is the predominant FGFR isoform present in human hepatocytes (Kan et al., 1999); we have also previously reported that liver tissue has the highest transcript levels of FGFR4 (Lin et al., 2007). In addition to FGFR4 being overexpressed in liver carcinomas (as well as several other types of human tumors), several missense genetic alterations have been observed in HCC patient samples; notably, a highly frequent G388R single nucleotide polymorphism in FGFR4 (associated with reduced survival for head and neck carcinoma, as well as a more aggressive phenotype for colon, soft tissue, prostate, and breast carcinomas) was identified (Ho et al., 2009). Furthermore, it has been previously demonstrated that ectopic expression of FGF19 (i.e. FGFR4-specific ligand) in mice promotes hepatocyte proliferation, hepatocellular dysplasia, and neoplasia (Nicholes et al., 2002).
It is clear that there continues to be a need for agents that have clinical attributes that are optimal for development as therapeutic agents. The invention described herein meets this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.